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PubMed2006

Spray-dried animal plasma prevents the effects of Staphylococcus aureus enterotoxin B on intestinal barrier function in weaned rats.

In this study, we investigated intestinal barrier function during inflammation as well as the effects of dietary supplementation with porcine spray-dried animal plasma (SDAP) proteins and porcine immunoglobulin concentrate (IC). Wistar Lewis rats were fed from d 21 (weaning) until d 34 or 35 either a control diet or a diet containing SDAP or IC. On d 30 and d 33, rats received an intraperitoneal dose of Staphylococcus aureus enterotoxin B (SEB; 0.5 mg/kg body wt; groups SEB, SEB-SDAP, and SEB-IC). SEB reduced the potential difference across the jejunum by 60%, the short-circuit current by 70%, and Na-K-ATPase activity in intestinal mucosa (all P < 0.05). The fluxes of dextran flux (4 kDa) and horseradish peroxidase (HRP, 40 kDa) across the intestinal wall also increased in SEB-treated rats (P < 0.01, P = 0.068, respectively). SEB also increased HRP flux across the paracellular space (P < 0.05). Moreover, SEB-treated rats had a reduced expression of tight junction proteins, such as ZO-1 (10% reduction; P < 0.05) and beta-catenin (20% reduction; P < 0.05). Dietary supplementation with SDAP or IC prevented dextran (P < 0.05) and HRP (P < 0.05) paracellular flux across the intestinal epithelium. SDAP supplementation also prevented SEB effects on Na-K-ATPase activity (P < 0.05). In our model of SEB-induced intestinal inflammation, the increased permeability across the intestinal mucosa was due to the lower expression of tight junction proteins, an effect that can be prevented by both SDAP and IC supplementation.

Animal Feed↗
PubMed2000

Effect of spray drying temperature of yoghurt on the survival of starter cultures, moisture content and sensoric properties of yoghurt powder.

A synergistic set of the strains Lactobacillus delbrueckii subsp. bulgaricus 151 and Streptococcus thermophilus MK-10 was preserved with the method of spray drying. Studies were performed on the effect of outlet air temperature in range of 60-80 degrees C upon the survival of yoghurt cultures, as well as the moisture content and sensoric properties of yoghurt powder. Survival of yoghurt cultures was the highest at 60 and 65 degrees C, but excessive moisture (10.2%) of yoghurt powder had a negative effect on its texture. Moisture content of the powder was low at 80 degrees C (4.4%), unfortunately sensoric faults appeared at this temperature, and survival of bacteria cultures decreased considerably. Temperatures within the range 70-75 degrees C ensured satisfactory survival of yoghurt cultures (L. delbrueckii subsp. bulgaricus--13.7-15.8%; S. thermophilus--51.6-54.7%), maintained proportion of the strains (L:S--1:3), satisfactory moisutre content (5.1-6.3%), and good sensoric properties of yoghurt powder.

Chemical Phenomena↗
PubMed2002

Effect of spray-dried plasma and lipopolysaccharide exposure on weaned pigs: II. Effects on the hypothalamic-pituitary-adrenal axis of weaned pigs.

A study was conducted with 20 weaned barrows (14 d, 4.98 +/- 0.21 kg) to determine the effect of feeding spray-dried plasma (SDP) after weaning on the pig's stress response to a lipopolysaccharide (LPS) challenge. After weaning, pigs were fed a diet containing 0 or 7% SDP for 7 d. On d 6 after weaning, all pigs were nonsurgically fitted with a jugular catheter. On d 7 after weaning, the pigs were given i.p. injections of either saline or LPS (150 microg/kg BW) followed by serial blood collection every 15 min for a 3-h period. Following the 3-h blood collection, all pigs were killed and tissue was collected for mRNA analysis. Pig weight on d 7 after weaning was not affected by dietary treatment (P > 0.21). Pigs fed the diet with SDP had lower (P < 0.05) levels of hypothalamic corticotropin-releasing hormone (CRH) mRNA, pituitary gland CRH receptor mRNA, and adrenal gland adrenocorticotropin-releasing hormone (ACTH) receptor mRNA. Dietary treatment did not affect pituitary gland proopiomelanocortin (POMC) mRNA. No effect of LPS treatment was observed in any of the mRNA levels examined. For both serum ACTH and cortisol, there was a significant diet x LPS treatment interaction (P < 0.01) such that both the ACTH and cortisol responses to the LPS challenge were greater in the pigs fed the diet with SDP than in the pigs fed the diet without SDP. For pigs given the saline injection, diet did not affect basal serum cortisol concentration; however, basal serum ACTH concentration was lower in those pigs fed the diet with SDP (P < 0.0001). A diet x LPS treatment interaction (P < 0.024) was observed for adrenal gland mRNA expression for steroidogenic acute regulatory (StAR) protein such that the LPS-induced increase in StAR mRNA was greater in the pigs fed SDP than in pigs fed the diet without SDP. These results demonstrate that pigs fed a diet with SDP have an increased activation of the pituitary-adrenal axis following an LPS challenge compared to pigs fed a diet without SDP.

Animals↗
PubMed2006

Sodium pantoprazole-loaded enteric microparticles prepared by spray drying: effect of the scale of production and process validation.

Pantoprazole is a prodrug used in the treatment of acid related disorders and Helicobacter pylori infections. It is activated inside gastric parietal cells binding irreversibly to the H(+)/K(+)-ATPase. In this way, pantoprazole must be absorbed intact in the intestinal tract, which indicates that enteric drug delivery systems are required for its oral administration. The purpose of this study was to investigate the physical characteristics of enteric pantoprazole-loaded microparticles prepared by spray drying using a blend of Eudragit S100 and HPMC. The microparticles were produced in different spray dryers and operational conditions at laboratory and pilot scales. Microparticles produced with two fluid nozzle atomizer and air pressure of 196 kPa presented satisfactory encapsulation efficiency and gastro-resistance. Microparticles produced with the same atomizer but using 49 kPa of air pressure presented strings in the powder. The microparticles produced in mixed flow presented very high polydispersity and the ones produced with rotating disc atomizer presented drug crystals adsorbed on the particle surfaces. The microparticles produced with two fluid nozzle atomizer and 196 kPa were prepared in three consecutive days for the process validation. The powders showed reproducible diameter, polydispersity, densities, encapsulation efficiency and gastro-resistance profile.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2002

Comparative physicochemical properties of hydrocortisone-PVP composites prepared using supercritical carbon dioxide by the GAS anti-solvent recrystallization process, by coprecipitation and by spray drying.

Hydrocortisone-PVP composites were successfully prepared using the supercritical fluid gas anti-solvent method (GAS). Analysis by differential scanning calorimetry DSC and powder X-ray diffraction (XRD) indicated that these systems were more crystalline than corresponding systems prepared by spray drying. These systems, prepared by the GAS method were more similar in physicochemical properties to coprecipitates prepared by conventional solvent evaporation. Compressed composites of hydrocortisone-PVP systems, prepared by the GAS method, had dissolution rates lower than those of corresponding systems prepared by the other processing methods but equivalent to those of corresponding physical mixtures.

Carbon Dioxide↗
PubMed1998

Optimization of an effervescent tablet formulation containing spray dried L-leucine and polyethylene glycol 6000 as lubricants using a central composite design.

A rotatable central composite design is used to evaluate the effects of lubricants and compression force on the physical characteristics of effervescent tablets. Effervescent tablets lubricated with a combination of spray dried L-leucine and polyethylene glycol 6000 are prepared by direct compression and examined. Residual force, crushing strength and disintegration time are considered as response variables and related to the L-leucine and polyethylene glycol concentrations and to the compression force. The calculated models are used to assess the influence of the production factors on tablet properties. As increasing amounts of L-leucine, showing good lubricating properties, reduce the crushing strength and prolong tablet disintegration, the L-leucine concentration is kept at a low level. An optimum tablet formulation contains 2% L-leucine and 3% polyethylene glycol 6000. The tablets have a tensile strength of 0.47 MPa and disintegrate in less than 2 min. Predicted and experimental results are in agreement within a 95% CI.

Chemistry, Pharmaceutical↗
PubMed2006

In situ coating--an approach for particle modification and encapsulation of proteins during spray-drying.

In this paper, we present a method for in situ coating of individual protein particles in a respirable size. The aim of the coating was to influence the particle/powder properties, and to reduce or prevent surface-induced conformational changes of the protein, during spray-drying, which was the method used for simultaneously preparing and coating particles. The investigated formulations included bovine serum albumin (BSA), trehalose and either of the two non-ionic polymers, hydroxypropyl methylcellulose (HPMC) and poly(ethylene oxide)-poly(propylene oxide) triblock co-polymer (Poloxamer 188). Complete protein coating as measured by electron spectroscopy for chemical analysis (ESCA) was achieved at a polymer concentration of approximately 1% of the total solids weight, and could be predicted from the dynamic surface tension at the air/water interface, as measured by the pendant drop method. Further, particle properties such as: size, dissolution time, powder flowability, and apparent particle density, as measured by gas pycnometry, were affected by the type and concentration of the polymer. In addition, the particle surface morphology could possibly be correlated to the surface elasticity of the droplet surface during drying. Moreover, an extensive investigation (Fourier transform infrared spectroscopy, circular dichroism and size exclusion chromatography) of the structural effects of protein encapsulated in a polymeric coating suggested that in situ coating provide particulate formulations with preserved native conformation and with a high stability during rehydration.

Calorimetry, Differential Scanning↗
PubMed2006

Evaluation of spray-dried lignin-based formulations and adjuvants as solar protectants for the granulovirus of the codling moth, Cydia pomonella (L).

Commercial formulations of the codling moth, Cydia pomonella L., granulovirus (CpGV) are limited by their short residual activity under orchard conditions in the Pacific Northwest. We evaluated spray-dried lignin-encapsulated formulations of CpGV for improved solar stability based on laboratory bioassays with a solar simulator and in field tests in an infested apple orchard. In laboratory tests, aqueous lignin formulations containing a high dosage of 3 x 10(10) occlusion bodies (OB)/L, with and without the additives titanium dioxide (TiO(2)) and sugar, provided significant solar protection of virus, i.e., mortality of codling moth exposed to lignin formulations that had been irradiated with 9.36 x 10(6) joules/m(2) was 92-94%, compared with 66-67% from a glycerin-stabilized product (Cyd-X) or suspension of pure unformulated virus at the same rates. By comparison, a lower dosage of the lignin formulation (3 x 10(8)OB/L) did not provide significant solar protection. Equivalent dosage-dependent patterns in solar protection were observed in further tests with the lignin formulation, when an intermediate (3 x 10(9)OB/L) as well as the low dosage provided no solar protection. Equivalent rates of a blank lignin formulation (containing no virus) did not affect larval mortality, suggesting a protective effect of the lignin on the virus at the high rate. The use of several spray adjuvants, 'NuFilm-17' and 'Organic Biolink' (sticker-spreaders at 0.06% v/v), 'Raynox' (sunburn protectant at 5% v/v), and 'Trilogy'(neem oil at 1% v/v) did not provide solar protection of a commercial CpGV preparation in laboratory tests. In season long orchard tests (Golden Delicious), the lignin formulation of CpGV applied at 6.57 x 10(12)OB/ha did not significantly improve control of codling moth or protection of fruit compared with Cyd-X at equivalent rates. Our studies show that lignin-based CpGV formulations provided solar protection at relatively high virus dosages. The testing of lignin formulations containing reduced virus concentrations may allow virus solar protection to be achieved at more economical rates.

Animals↗
PubMed1980

Resistance of 17 mesophilic lactic Streptococcus bacteriophages to pasteurization and spray-drying.

For 17 phages active against Streptococcus cremoris, Str. lactis and Str. lactis subsp. diacetylactis, the killing efficiency of pasteurization (log No/N) at 72 degrees C for 15 s in skim-milk showed large variations from greater than 6 to 0; the efficienty of killing during spray-drying ranged from 3.7 to 0.2 and phages survived well storage of milk powder at room temperature. Destruction in a heat exchanger was found to be greater than that calculated from biphasic curves obtained by heating phages in sealed ampoules. No relationship was established between lytic classification of phages and their heat resistance.

Animals↗
PubMed2004

Impact of spray-dried bovine serum and environment on turkey performance.

Two 28-d experiments were conducted with 280 and 224 Hybrid turkeys for experiments 1 (7 poults per pen, 10 pens per treatment) and 2 (7 poults per pen, 8 pens per treatment), respectively. The effect of Innavax (INX; spray-dried serum) administered in drinking water on turkey performance was evaluated. In both experiments, turkeys were randomly assigned to receive tap water mixed with 0, 0.45, 0.90, or 1.35% (wt/wt) INX and housed in floor pens containing clean (experiment 1) or used (experiment 2) litter. In experiment 1, a quadratic response in average daily gain (ADG), water intake, and feed efficiency occurred (P < 0.05) in the first week with increasing levels of INX. During the second and third weeks, a quadratic response in water intake occurred (P < 0.05) with 0.90% INX resulting in peak intake. In the fourth week, ADG increased quadratically (P < 0.05) with increasing INX. Overall for the 4-wk period, ADG and water intake increased quadratic manner (P < 0.05) with increasing INX to a maximum at 0.90%. In experiment 2, ADG and water intake increased linearly (P < 0.05) during the first week. Feed efficiency was unaffected (P > 0.05) by experimental treatment during the first week but increased linearly (P < 0.05) from d 8 to 14 and d 15 to 21. The growth response to INX was influenced by environment. A greater growth response of turkeys to INX was observed when turkeys were housed in floor pens with used litter compared with floor pens with clean litter.

Administration, Oral↗
PubMed2005

5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: characterization and drug release.

5-Fluorouracil (5-FU), a hydrosoluble anti-neoplastic drug, was encapsulated in microspheres of poly(D,L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) polymers using the spray-drying technique, in order to obtain small size microspheres with a significant drug entrapment efficiency. Drug-loaded microspheres included between 47 +/- 11 and 67 +/- 12 microg 5-FU mg(-1) microspheres and the percentage of entrapment efficiency was between 52 +/- 12 and 74 +/- 13. Microspheres were of small size (average diameter: 0.9 +/- 0.4-1.4 +/- 0.8 microm microspheres without drug; 1.1 +/- 0.5-1.7 +/- 0.9 microm 5-FU-loaded microspheres) and their surface was smooth and slightly porous, some hollows or deformations were observed in microspheres prepared from polymers with larger Tg. A fractionation process of the raw polymer during the formation of microspheres was observed as an increase of the average molecular weight and also of Tg of the polymer of the microspheres. The presence of 5-FU did not modify the Tg values of the microspheres. Significant interactions between the drug and each one of the polymers did not take place and total release of the included drug was observed in all cases. The time needed for the total drug release (28-129 h) was in the order PLA > PLGA 75/25 > PLGA 50/50. A burst effect (17-20%) was observed during the first hour and then a period of constant release rate (3.52 +/- 0.82-1.46 +/- 0.26 microg 5-FU h(-1) per milligram of microspheres) up to 8 or 13 h, depending on the polymer, was obtained.

Antimetabolites, Antineoplastic↗
PubMed2000

Sunlight persistence and rainfastness of spray-dried formulations of baculovirus isolated from Anagrapha falcifera (Lepidoptera: Noctuidae).

Nuclear polyhedrosis viruses such as the one isolated from the celery looper, Anagrapha falcifera (Kirby) (AfMNPV), have the potential to be successful bioinsecticides if improved formulations can prevent rapid loss of insecticidal activity from environmental conditions such as sunlight and rainfall. We tested 16 spray-dried formulations of AfMNPV to determine the effect of different ingredients (e.g., lignin, corn flour, and so on) on insecticidal activity after simulated rain and simulated sunlight (at Peoria, IL) and natural sunlight exposures (at Tifton, GA). The most effective formulation contained pregelatinized corn flour and potassium lignate, which retained more than half of its original activity after 5 cm of simulated rain, and almost full activity after 8 h of simulated sunlight. In Georgia, formulations made with and without lignin were compared for persistence of insecticidal activity when exposed to natural sunlight. In addition, the effect of fluorescent brighteners as formulation components and spray tank additives was tested. Results showed that the formulations with lignin had more insecticidal activity remaining after sunlight exposure than formulations without lignin. The inclusion of brighteners in the formulation did not improve initial activity or virus persistence. However, a 1% tank mix significantly enhanced activity and improved persistence. Scanning electron micrographs revealed discreet particles, and transmission electron micrographs showed virus embedded within microgranules. Results demonstrated that formulations made with natural ingredients could improve persistence of virus-based biopesticides.

Animals↗
PubMed2002

Fabrication and properties of spray-dried nanofeatured spherical Ni(OH)2 materials.

Spherical agglomerates of nanostructured beta-phase Ni(OH)2 with the general formula Ni1-xCox(OH)2 (x = 0, 0.1, 0.3) for use as cathode materials were produced by a modified method including coprecipitation of Ni or Ni composite hydroxide and further spray drying of the precipitated and washed slurry. This process leads to the formation of spherical agglomerate particles with a narrow Gaussian-type distribution range. The method permits faster and cheaper production of cathode materials with a higher specific surface area and similar or better capacity and cycle life compared with the materials prepared via conventional technology.

Aerosols↗
PubMedDate not supplied

Spray-dried albumin microspheres for the intra-articular delivery of dexamethasone.

This work deals with the preparation of corticosteroid-loaded albumin microspheres designed for intra-articular administration. Dexamethasone was chosen as the model drug and bovine serum albumin was used as the biodegradable, natural polymer. Albumin microspheres were produced by spray drying, a 'one-step' technique seldom used in the preparation of microparticulate drug delivery systems with particle sizes < 10 microns. The effects of both polymer/drug ratio used in the formulations and the different heat-stabilization conditions were evaluated on morphology, size, solubility characteristics, drug loading and 'in vitro' drug release of the microparticles.

Dexamethasone↗
PubMed2004

Moisture-induced surface crystallization of spray-dried amorphous lactose particles studied by atomic force microscopy.

The aim of this study was to show that atomic force microscopy (AFM) can be used to obtain mechanistic and kinetic information about the process of moisture-induced surface crystallization of single particles of amorphous lactose. Completely amorphous lactose particles were prepared by spray-drying a solution of alpha-lactose monohydrate, and moisture-induced crystallization was monitored for a bed of particles by microcalorimetry and for single particles by AFM. From the AFM images it was found that crystallization of the surface of single particles can be described in terms of a sequence of three events: an initial smoothening of the surface, formation of crystalline nanostructures dispersed in amorphous material, and growth of these structures to a complete crystalline surface. The surface roughness parameter rugosity was used to estimate the fraction crystalline surface, and the growth kinetics were found to obey the JMAK equation. The fraction crystalline surface at different times could also be estimated by determining the growth rate of individual crystals. It was concluded that AFM offers a unique means of visualizing the process of moisture-induced surface crystallization of amorphous particles and enables mechanistic and kinetic information about the process to be extracted.

Calorimetry↗
PubMed2003

The effects of thermal environment and spray-dried plasma on the acute-phase response of pigs challenged with lipopolysaccharide.

Forty barrows (TR4 x C22) were weaned at 17 d of age (BW = 6.27 +/- 0.30 kg), housed (two pigs/pen) in a thermal-neutral environment (TN; constant 26.7 degrees C), and fed diets with or without 7% (as-fed basis) spray-dried plasma (SDP). On d 7, one pig/ pen was moved into a cold environment (CE; constant 15.6 degrees C). Pigs were fitted with jugular catheters on d 11. On d 12, 16 pigs per environment (eight pigs per dietary treatment) were challenged i.v. with 75 microg of lipopolysaccharide (LPS)/kg of BW. Blood samples were collected over a 4.5-h period. Pigs were then killed and tissue samples were harvested for messenger RNA (mRNA) analysis. From d 0 to 7, pigs fed SDP diets had a lower gain:feed ratio (G/F) than pigs fed no SDP (533 +/- 14 vs. 585 +/- 17 g/kg; P < 0.03). Pigs housed in the CE consumed more feed and had a lower G/F than pigs housed in TN from d 7 to 11 (P < 0.001). There were no environment x diet interactions from d 7 to 11 (P > 0.78). Baseline concentrations of serum ACTH and cortisol were lower in the TN pigs than in the CE pigs (P < 0.001). Pigs fed diets without SDP had lower serum cortisol concentrations over the 4.5-h period than pigs fed SDP (time x diet, P < 0.001). Serum concentrations of tumor necrosis factor-alpha (TNF-alpha) were highest for pigs consuming SDP in the CE, whereas there were no differences among the other treatments (time x diet x environment, P < 0.02). Pigs housed in the CE had higher serum interleukin-1beta (IL-1beta) (P < 0.001) and interleukin-6 (IL-6; P < 0.001) than TN pigs. Pigs fed SDP also had slightly higher serum IL-1beta concentrations (P < 0.10) and higher (P < 0.001) IL-6 concentrations than pigs fed no SDP. Pigs fed SDP had 9% lower liver and 13% lower thymus mRNA expression of tumor necrosis factor-alpha (TNF-alpha) than pigs that consumed no SDP (P < 0.06). Liver IL-1beta, IL-6, and LPS-binding protein mRNA were higher in the CE than in the TN (P < 0.03, P < 0.001, and P < 0.05; respectively). In addition, spleen TNF-alpha (P < 0.03) and IL-6 (P < 0.01) mRNA levels were higher in the CE than in the TN. Pigs consuming SDP and challenged with LPS responded with elevated serum concentrations of cortisol and cytokines compared with pigs fed diets with no SDP. Housing pigs in a CE increased the baseline concentrations of ACTH and cortisol, and when coupled with an LPS challenge, resulted in elevated serum and tissue mRNA levels of cytokines. Cold stress and feeding SDP during a LPS challenge may result in increased stress and immune responses in young pigs.

Acute-Phase Proteins↗
PubMed1985

Zinc requirement of the baby pig when fed wet-autoclaved spray-dried egg albumen as the protein source.

Pigs 16 d of age were allotted to eight dietary levels of total zinc (6-36 ppm in 5 ppm increments and 116 ppm) in a 28-d experiment designed to reevaluate the zinc requirement of the neonatal pig. The basal 21.0% crude protein diet contained wet-autoclaved spray-dried egg albumen (WAEA) as the protein source. Dietary zinc level did not affect (P greater than 0.05) pig growth for the first 14 d of the experiment. Pig growth was adequate from d 14 to 28 of the experiment with 11 ppm or more of zinc. The milligrams of zinc retained per day per pig increased (P less than 0.05) with increasing dietary zinc up to 26 ppm, plateaued from 26 to 36 ppm and declined (P less than 0.05) at 116 ppm. Plasma zinc levels were higher (P less than 0.05) for pigs fed 31 ppm or more of zinc compared with 16 ppm or less of zinc on d 21 and 28. Tibia and femur concentrations of zinc also increased with increasing dietary zinc up to 26 ppm. Esophageal tissue was normal in the majority of pigs fed 31 ppm or more of zinc. Retention of 65Zn further suggested that diets containing 26 ppm or less zinc were deficient in this element. Thus, zinc balance, concentrations of zinc in plasma and bone, esophageal histology and retention of 65Zn indicate that the minimum zinc requirement of the neonatal pig is between 26 and 31 ppm when fed a purified diet devoid of phytate.

Albumins↗
PubMed2002

Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep.

Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine-polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 microg epinephrine, with the addition of 150 microg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53+/-0.53 l/min and the mean elimination half-life was 120.5+/-73.1 min. Following brachial plexus nerve injection, bupivacaine C(max) were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8+/-1.0 h (bupivacaine alone) compared to 24.6+/-1.2 h following microsphere administration.

Anesthetics, Local↗